The immune response is important in clinical aspects of diabetes. Patients treated with insulin often develop antibodies to insulin. Such antibodies have been associated with relative resistance to insulin treatment. Furthermore, some cases of juvenile onset diabetes probably are related to autoimmunity against antigens of insulin-secreting pancreatic islet cells, and spontaneous immune responses against insulin have also been noted. We have been studying the immune response of mice against defined antigenic determinants of various insulins. The response of T lymphocytes to defined foreign or self-determinants was influenced by three factors: the immune response genes of the mice both within and without the H-2 complex; the mode of immunization via macrophages or adjuvant; and the cooperativity between different antigenic determinants of insulin. The objective of the proposed research is to identify the immune mechanisms controlling the reactivity against antigenic determinants of insulin. This will serve as a foundation for developing an animal model of autoimmunity to insulin mediated by T lymphocytes. Clinical consequences of this autoimmunity will be studied with particular attention to insulitis and autoreactive antibodies.